Study on the functionalization and reactivity of bicyclic acetal compounds

Article abstract of DOI:10.1081/SCC-120001507

Bicyclic acetal was known as a versatile reagent for the structural transformation reactions. Bicyclic acetal was functionalized to the acetal-lactol and halo-lactol, and applied for the new rearrangement reactions. The structural identification and rearrangement mechanism were discussed herein.

Full text of DOI:10.1081/SCC-120001507

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STUDY ON THE FUNCTIONALIZATION AND REACTIVITY
OF BICYCLIC ACETAL COMPOUNDS
Jong-Gab Jun , Ae-Ran Kim a & Sung Hoon Kim b
a Department of Chemistry, Hallym University , Chunchon, 200-702, Korea
b Department of Chemistry, Konkuk University , Seoul, Korea
Published online: 21 Aug 2006.
To cite this article: Jong-Gab Jun , Ae-Ran Kim & Sung Hoon Kim (2002) STUDY ON THE FUNCTIONALIZATION AND
REACTIVITY OF BICYCLIC ACETAL COMPOUNDS, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 32:1, 45-52, DOI: 10.1081/SCC-120001507
To link to this article: http://dx.doi.org/10.1081/SCC-120001507
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SYNTHETIC COMMUNICATIONS, 32(1), 45–52 (2002)
STUDY ON THE FUNCTIONALIZATION
AND REACTIVITY OF BICYCLIC
ACETAL COMPOUNDS
Jong-Gab Jun,1, Ae-Ran Kim,1
*
and Sung Hoon Kim2
1Department of Chemistry, Hallym University,
Chunchon 200-702, Korea
2Department of Chemistry,
Konkuk University, Seoul, Korea
ABSTRACT
Bicyclic acetal was known as a versatile reagent for the struc-
tural transformation reactions. Bicyclic acetal was functiona-
lized to the acetal-lactol and halo-lactol, and applied for the
new rearrangement reactions. The structural identification
and rearrangement mechanism were discussed herein.
A versatile transformation utility of bicyclic acetals in the 6,8-dioxa-
bicyclo[3.2.1]octane structure have been reported for the direct synthesis of
1,5-diketone,1 cis-1,2-cyclopentanediol,2 2,6-disubstituted pyridine,3 2,3,6-
trisubstituted pyridine,4 cyclohexenone,5 and allylic acetate derivatives.6
In the continuous study of developing new chemistry utilizing bicyclic
acetals, the acetal-lactol and halo-lactol were prepared and reacted with
base to give the new rearrangement reactions.
*Corresponding author.
45
Copyright & 2002 by Marcel Dekker, Inc.
www.dekker.com

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JUN, KIM, AND KIM
The bicyclic acetal-lactol 1 was obtained in 80% yield by using
DIBAH reduction7 from the acetal-lactone 2 as shown in Scheme 1.
Dilution technique was used for the hetero Diels-Alder reaction.8 The reac-
tion of 3 equiv. of MVK 3 and 1 equiv. of methyl metacrylate (4) gave 8 : 2
ratio of pyrans 5 and 6 respectively. The ester 5 was hydrolyzed with NaOH
and cyclized with HCl to give acetal-lactone 2 in 94% yield.
Scheme 1.
The acetal-lactol 1 was refluxed with NaH/THF or t-BuONa/t-BuOH
and found a novel rearrangement to give acetyl-cyclopentene 7 in 89% and
82% yield respectively. The reaction mechanism was proposed as shown in
Scheme 2. The lactol proton was deprotonated by base and ring opening
was followed to give ketone-aldehyde 8 which was recyclized via aldol con-
densation yielding the acetyl-cyclopentene 7.
We applied this reaction with 4-iodolactol and 7-phenyllactol, but
obtained no reaction. 4-Bromolactol 10, however, which was prepared as
a single isomer (equatorial)9 via halolactonization10 from the ester 5 or via
direct bromination11 from the lactone 2 gave debromonated-t-butoxide
substituted product in 63% yield by using t-BuONa/t-BuOH as shown in
Scheme 3. Spectroscopic analysis could not distinguish the product from the
two possible debromonated products 11 and 12.

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BICYCLIC ACETAL COMPOUNDS
47
Scheme 2.
Scheme 3.
The plausible mechanisms for the two possible products 11 and 12
were showed in Scheme 4. The deprotonation of bromo-lactol 10 was
same as acetal-lactol 1, but epoxidation was followed in bromo-lactol
instead of aldol condensation in acetal-lactol. The epoxide-aldehyde 13
was the intermediate for the two possible products. If t-butoxide attacks
the aldehyde as a nucleophile followed by epoxide opening should give the

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JUN, KIM, AND KIM
Scheme 4.
4-hydroxy acetal 11, but attacks the epoxide and following acetalization
should gives the 4-t-butoxy acetal 12.
The nmr chemical shift of H-4 shows at 3.46 ppm and H-7 shows at
4.98 ppm in the product. Acetylation of the product should change the
chemical shift of the hydroxy attached proton and we found the chemical
shift change from 3.46 ppm to 4.64 ppm after acetylation as shown in
Scheme 5. This result indicates that the right structure of debromonated
t-butoxide product is the 4-hydroxy acetal 11. The stereostructure of the
single isomer 11 could be an equatorial because of steric effect.9
Scheme 5.
The reaction of bromo-lactol 10 with NaH did not give the expected
product 15, but gave mostly starting material back with some decomposed
products.

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49
Scheme 6.
In conclusion, acetal-lactols were easily prepared and rearranged to
cyclopentene or 4,7-dioxygenated acetal by using t-butoxide depend on sub-
stituent at C-4.
EXPERIMENTAL
The NMR spectra were recorded on a Varian Gemini-200 MHz
FT-NMR, with the chemical shifts (d) reported in parts per million (ppm)
relative to TMS and the coupling constants (J ) quoted in Hz. CDCl3 was
used as a solvent and an internal standard. Infrared spectra were recorded
on a Shimadzu IR-435 spectrometer. GLC analyses were performed using a
Shimadzu CG-7A equipped with a 11 ft ꢀ 1/4 in, 10% OV-17 column. Most
of the chemicals were purchased from Aldrich and were used without
further purification unless noted otherwise. Flash chromatography was
carried out using silica gel Merck 60 (230–400 mesh). Thin-layer chromato-
graphy (TLC) was performed on DC-Plastikfolien 60, F254 (Merck, layer
thickness 0.2 mm) plastic-backed silica gel plates with visualization by UV
light (254 nm) or by treatment with p-anisaldehyde.
2-Methoxycarbonyl-2,6-dimethyl-3,4-dihydro-2H-pyran (5). A solution
of methyl vinyl ketone 3 (12.0 mL, 0.14 mol), methyl metacrylate 4 (45.0 mL,
0.42 mol), hydroquinone (0.40 g, 3.63 mmol) in 150 mL of benzene was
placed in a steel pressure bomb and heated at 170ꢁC for 3 h. After cooling,
the solvent was removed via a rotatory evaporator and the product was
distilled to give 20.30 g of 2-methoxycarbonyl-2,6-dimethyl-3,4-dihydro-
1
2H-pyran (5) and MVK dimer 6 as a 8 : 2 ratio. H NMR (CDCl3) d 4.50
(1H, br s, ¼CH), 3.74 (3H, s, OCH3), 2.15–1.93 (4H, m, CH2CH2), 1.79 (3H,
br s, ¼CCH3), 1.49 (3H, s, OCCH3); 13C NMR (CDCl3) d 172.8 (C¼O),
148.2 (¼C-O), 93.6 (C-O), 76.0 (C¼), 50.6 (OCH3), 28.4 (CH3), 23.3 (CH2),
18.4 (CH2), 16.7 (CH3); IR(neat): 1756 (C¼O), 1687 (C¼C-O), 1449, 1313,
1241, 1120, 1069 cmÀ1
.
1,5-Dimethyl-6,8-dioxabicyclo[3.2.1]octan-7-one (2). The mixture (2.0 g,
9.4 mmol) of 2-methoxycarbonyl-2,6-dimethyl-3,4-dihydro-2H-pyran (5)

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JUN, KIM, AND KIM
and MVK dimer 6 as a 8 : 2 ratio was added slowly to a solution of NaOH
(1.5 g, 37.5 mmol) in water (25 mL), stirred for 12 h and extracted with ether
(50 mL ꢀ 3). After the ether layer which contains MVK dimer 6 was removed,
the water layer was acidified with 6N HCl (20 mL) and was extracted with
ether (30 mL ꢀ 4). The combined organic layer was washed with NaHCO3,
brine, dried over MgSO4, concentrated and chromatographed (ether :
hexane ¼ 1:1) to give a yellow oil (1.4 g, 94%). 1H NMR (CDCl3) d
1.85–1.60 (6H, m, CH2CH2CH2), 1.58 (3H, s, C5-methyl), 1.42 (3H, s,
C1-methyl); 13C NMR (CDCl3) d 175.6 (s, C¼O), 109.4 (s, O-C-O), 80.3 (s,
C-O), 30.7 (t), 30.3 (t), 23.5 (q), 20.4 (q), 17.4 (t); IR (neat): 1790, 1745, 1463,
1393, 1361, 1283, 1254, 1225, 1121, 1040, 947, 897, 871, 827 cmÀ1
.
7-Hydroxy-1,5-dimethyl-6,8-dioxabicyclo[3.2.1]octane (1). To a stirred
solution of acetal-lactone 2 (0.1 g, 0.64 mmol) in dry THF (3 mL) at À 20ꢁC
was added DIBAH (1.50 mmol) slowly and stirred for 1 h at À 20ꢁC. Water
(30 mL) was added to the reaction bottle and extracted with ethyl acetate
(30 mL ꢀ 4). The combined organic layer was washed with NaHCO3, brine,
dried over MgSO4, concentrated and chromatographed (ethyl acetate :
1
hexane ¼ 2 : 1) to give a yellow oil (0.08 g, 80%). H NMR (CDCl3) d 5.14
(1H, s), 2.61 (1H, s), 1.80–1.45 (6H, m), 1.58 (3H, s), 1.29 (3H, s); IR (neat):
.
3424, 1460, 1385, 1250, 1214, 1118, 999, 848, 732 cmÀ1
1-Acetyl-3-hydroxy-3-methylcyclopentene (7). (Method A) To a stirred
solution of t-BuONa (0.02 g, 0.22 mmol) in t-BuOH (3 mL) under N2 atmos-
phere was added acetal-lactol 1 (0.01 g, 0.06 mmol) and refluxed for 20 min.
After evaporation of t-BuOH, ether (15 mL), water (2 mL) and 3N HCl
(15 mL) were added to the reaction mixture and extracted with ethyl acetate
(20 mL ꢀ 4). The combined organic layer was washed with NaHCO3, brine,
dried over MgSO4, concentrated and chromatographed (ethyl acetate :
hexane ¼ 2 : 1) to give a yellow oil (0.007 g, 82%).
(Method B) To a stirred solution of NaH (0.004 g, 0.15 mmol) in dry
THF (1 mL) under N2 atmosphere at 0ꢁC was added acetal-lactone 1 (0.02 g,
0.13 mmol) and refluxed for 30 min. Water (2 mL) was added to the reaction
mixture and extracted with ethyl acetate (20 mL ꢀ 3). The combined organic
layer was washed with NaHCO3, brine, dried over MgSO4, concentrated and
chromatographed (ethyl acetate : hexane ¼ 2:1) to give a yellow oil (0.016 g,
89%). 1H NMR (CDCl3) d 6.51 (1H, br s, ¼ CH), 2.70–2.45 (2H, m), 2.34 (3H,
s,COCH3),2.05–1.95(2H,m),1.67(1H,brs,OH),1.44(3H,s,CH3);13C NMR
(CDCl3) d 198.1 (C ¼ O), 147.6 (¼ CH), 145.2 (¼ C), 84.0 (COH), 40.0 (CH2),
29.3 (CH2), 27.3 (CH3), 27.2 (CH3); IR (neat): 3453 (OH), 1663 (C ¼ O), 1376,
1294,1102,1086,930 cmÀ1.Ms m/z140(Mþ),125,122(base),107,97,84,79,61.
4-Bromo-1,5-dimethyl-6,8-dioxabicyclo[3.2.1]octan-7-one (9). (Halo-
lactonization Method); The mixture8 (0.5 g, 2.94 mmol) of 2-methoxy-
carbonyl-2,6-dimethyl-3,4-dihydro-2H-pyran (5) and MVK dimer 6 as a

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BICYCLIC ACETAL COMPOUNDS
51
8 : 2 ratio was added slowly to a solution of NaOH (0.47 g, 11.75 mmol) in
water (15 mL), stirred for12 h and extracted with ether (30 mL ꢀ 3). After
the ether layer which contains MVK dimer 4 was removed, the water layer
was evaporated to dryness and mixed with aqueous NaHCO3 (0.75 g,
8.82 mmol). After 30 min stirring, Br2 (0.15 mL, 2.94 mmol) was added to
the aqueous layer and stirred for 3 h at rt and extracted with methylene
chloride (30 mL ꢀ 4). The combined organic layer was washed with 10%
aqueous Na2S2O3, brine, dried over MgSO4, concentrated and chromato-
graphed (ether : hexane ¼ 1:1) to give a pale yellow solid (0.42 g, 71%).
(Direct Bromination); To a stirred solution of Na2CO3 (0.24 g,
2.24 mmol) in CCl4 (10 mL) under N2 atmosphere were slowly added
acetal-lactone 2 (0.10 g, 0.64 mmol) and Br2 (0.04 mL, 0.7 mmol), and stirred
for 3 h at rt. Water (13 mL) was added to the reaction mixture and extracted
with methylene chloride (30 mL ꢀ 4). The combined organic layer was
washed with 10% aqueous Na2S2O3, brine, dried over MgSO4, concentrated
and chromatographed (ether : hexane ¼ 1:1) to give a pale yellow solid
(0.11 g, 73%). mp 72–75ꢁC, H NMR (CDCl3) d 4.13 (1H, br d, BrCH),
1
2.4–1.6 (4H, m), 1.77 (3H, s, C5-Me), 1.50 (3H, s, C1-Me); IR (KBr): 1808
(C ¼ O), 1449, 1411, 1278, 1252, 1164, 1127, 1079, 1037, 890, 860, 823,
767 cmÀ1
.
4-Bromo-7-hydroxy-1,5-dimethyl-6,8-dioxabicyclo[3.2.1]octane (10). To
a stirred solution of bromo-lactone 9 (0.1 g, 0.43 mmol) in dry THF (2.5 mL)
at À 20ꢁC was added DIBAH (1.06 mmol) slowly and stirred for 1 h at
À 20ꢁC. Water (30 mL) was added to the reaction bottle and extracted with
ether (30 mL ꢀ 4). The combined organic layer was washed with NaHCO3,
brine, dried over MgSO4, concentrated and chromatographed (ethyl acetate :
hexane ¼ 2 :1) to give a white solid (0.075 g, 75%). mp 120–122ꢁC, 1H NMR
(CDCl3) d 5.03 (1H, br d, HOCH), 3.93 (1H, br d, BrCH), 2.61 (1H, br d,
OH), 2.4–2.3 (2H, m), 2.1–1.9 (2H, m), 1.66 (3H, s, C5-Me), 1.35 (3H,
C1-Me); IR (KBr): 3361 (OH), 1467, 1383, 1262, 1196, 1125, 982, 856 cmÀ1
.
7-t-Butoxy-4-hydroxy-1,5-dimethyl-6,8-dioxabicyclo[3.2.1]octane (11).
To a stirred solution of t-BuONa (0.28 g, 2.95 mmol) in t-BuOH (20 mL)
under N2 atmosphere was added bromo-lactol 10 (0.20 g, 0.84 mmol) and
refluxed for 5 h. After evaporation of t-BuOH, 3N HCl (15 mL) were added
to the reaction mixture and extracted with ethyl acetate (20 mL ꢀ 4). The
combined organic layer was washed with NaHCO3, brine, dried over
MgSO4, concentrated and chromatographed (ethyl acetate : hexane ¼ 2 :1)
1
to give a yellow oil (0.12 g, 63%). H NMR (CDCl3) d 4.98 (1H, s, C7-H),
3.46 (1H, dd, J ¼ 9 and 7 Hz, C4-H), 1.9–1.75 (3H, m, CH2 and OH), 1.6–1.4
(2H, m), 1.45 (3H, s, C5-Me), 1.25 (9H, s, t-butyl), 1.19 (3H, s, C1-Me);
13C NMR (CDCl3) d 107.8 (5-C), 102.4 (7-CH), 80.2 (1-C), 75.3 (O-t-butyl
C), 71.6 (4-CH), 31.1 (3-CH2), 28.7 (t-butyl Me3), 28.2 (2-CH2), 22.0

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JUN, KIM, AND KIM
(5-CH3), 21.9 (1-CH3); IR (neat): 3436 (OH), 1451, 1391, 1368, 1207, 1134,
1075, 994, 882 cmÀ1. CIMs (NH3) m/z 248.
ACKNOWLEDGMENT
This work was supported by Korea Research Foundation Grant
(KRF-1999-015-DP0230).
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(b) Jun, J.-G.; Ha, T.H.; Mundy, B.P.; Bartelt, K.E.; Bain, R.S.;
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Received in Japan November 27, 2000

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